Development and validation of AI-assisted transcriptomic signatures to personalize adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment. PATIENTS AND METHODS: We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the 'Pancreas-View' tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial. RESULTS: Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months [stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001] and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively). CONCLUSIONS: This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.

Baseline nutritional status is prognostic factor after definitive radiochemotherapy for esophageal cancer.

Identify prognostic factors for survival and patterns of treatment failure after definitive radiochemotherapy for esophageal cancer. Between 2003 and 2006, 143 patients with squamous cell carcinoma and adenocarcinoma of the esophagus were retrospectively reviewed. Median age was 65 years (42-81). Median radiation dose was 62.5 Gy (38-72) with 1.8-2 Gy fraction. Median follow-up was 20.8 months (2.8-92.4). Three and 5-year local recurrence-free survival rates were 58.3% and 50.9%. In univariate analysis, traversable esophageal stricture was a prognostic factor. Three, 5-year locoregional recurrence-free survival rates were 42.4% and 34.9%. In multivariate analysis, traversable esophageal stricture and stage < IIB were independent prognostic factors. Three and 5-year disease-free survival rates were 30.5% and 25.9%. In multivariate analysis, Nutritional Risk Index (NRI) ≥ 97.5 and performance status (PS) = 0 were independent prognostic factors. Median, 3, and 5-year overall survival rates were 22.1 months, 34.4%, and 19.8%. In multivariate analysis, independent prognostic factors were NRI ≥ 97.5 and PS = 0. Median survival times for the NRI classes (no denutrition, moderate and severe denutrition) were 29.5, 19.7, and 12 months (P = 0.0004), respectively. A major impact of baseline NRI was found in terms of survival; it should be included in future prospective trials.

Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study.

BACKGROUND: Immunotherapy demonstrated remarkable efficacy in metastatic colorectal cancers (mCRCs) with mismatch repair deficiency (MMRd)/microsatellite instability (MSI). However, data regarding efficacy and safety of immunotherapy in the routine clinical practice are scarce. PATIENTS AND METHODS: This is a retrospective, multicenter study aiming to evaluate efficacy and safety of immunotherapy in routine clinical practice and to identify predictive markers for long-term benefit. Long-term benefit was defined as progression-free survival (PFS) exceeding 24 months. All patients who received immunotherapy for an MMRd/MSI mCRC were included. Patients who received immunotherapy in combination with another known effective therapeutic class agent (chemotherapy or tailored therapy) were excluded. RESULTS: Overall, 284 patients across 19 tertiary cancer centers were included. After a median follow-up of 26.8 months, the median overall survival (mOS) was 65.4 months [95% confidence interval (CI) 53.8 months-not reached (NR)] and the median PFS (mPFS) was 37.9 months (95% CI 30.9 months-NR). There was no difference in terms of efficacy or toxicity between patients treated in the real-world or as part of a clinical trial. Overall, 46.6% of patients had long-term benefit. Independent markers associated with long-term benefit were Eastern Cooperative Oncology Group-performance status (ECOG-PS) 0 (P = 0.025) and absence of peritoneal metastases (P = 0.009). CONCLUSIONS: Our study confirms the efficacy and safety of immunotherapy in patients with advanced MMRd/MSI CRC in the routine clinical practice. ECOG-PS score and absence of peritoneal metastases provide simple markers that could help identify patients who benefit the most from this treatment.

Continuation versus discontinuation of first-line chemotherapy in patients with metastatic squamous cell oesophageal cancer: A randomised phase II trial (E-DIS).

PURPOSE: The role of chemotherapy has not been established in the treatment of metastatic squamous cell oesophageal cancer (mESCC). PATIENTS AND METHODS: E-DIS is a discontinuation trial, aimed at estimating efficacy, quality of life and safety of chemotherapy continuation (CT-CONT) in patients with mESCC who are free from progression after a selection phase of chemotherapy. The primary end-point was overall survival. RESULTS: Sixty-seven patients were randomised. The 9-month survival rate was 50% (85% confidence interval [CI]: 37-62%) and 48% (85% CI: 35-60%) in the CT-CONT arm and in the chemotherapy discontinuation (CT-DISC) arm, respectively. The time until definitive deterioration of the global health status (European Organisation for Research and Treatment of Cancer [EORTC] core quality of life questionnaire) was 6.6 months (95% CI: 3.3-12.4) for the CT-CONT arm and 4.2 months (95% CI: 2.9-6.3) for the CT-DISC arm, with a hazard ratio (HRCT-DISC/CT-CONT) = 1.44 (95% CI: 0.82-2.53). We observed a beneficial trend in favour of CT-CONT (HR > 1) for most dimensions, including an improvement for three dimensions (dysphagia, eating and oesophageal pain) of the EORTC Oesophageal Cancer Module QLQ-OES18. CONCLUSION: CT-CONT provides an overall survival rate that is similar to CT-DISC. E-DIS trial provides valuable data to support shared decision-making between physicians and patients regarding CT-CONT/DISC.

[A urachus cyst revealing a torpid Crohn's disease in a young adult with chronic fever]. / Kyste de l'ouraque révélateur d'une maladie de Crohn torpide chez un adulte jeune atteint d'une fievre nue chronique.

INTRODUCTION: This case report describes a rare situation in which a superinfected cyst of the urachus complicated initially unknown and inactive Crohn's disease. CASE: A 21-year-old man presented a chronic fever finally attributed to a superinfected urachal cyst. Six months after ablation of the cyst, progressive Crohn's disease was diagnosed. DISCUSSION: The association of Crohn's disease and a superinfected urachal cyst is extremely rare. The case reported here is original in two aspects: the slowly progressive Crohn's disease was diagnosed after its complication; the superinfection developed through local bacterial translocation (ileal loop adjacent to the urachal cyst).

[Definitive chemoradiotherapy for esophageal cancer: 66Gy versus 50Gy, a retrospective study]. / Chimioradiothérapie exclusive pour cancer de l'œsophage : comparaison entre 66Gy et 50Gy, une étude rétrospective.

PURPOSE: To compare the influence of radiation dose, high dose versus standard dose, on survival for patients with esophageal carcinomas treated with definitive radiochemotherapy. PATIENTS AND METHODS: Between 2003 and 2006, 143 consecutive patients with squamous-cell carcinoma and adenocarcinoma, clinical stage I to IVA, treated in two different institutions were retrospectively reviewed, 83 patients had received more than 50.4Gy, median dose 66Gy (50.7-72Gy) and 60 less than or equal to 50.4Gy, median dose 50Gy (38-50.4Gy). RESULTS: Median age was higher in high dose group (67.6 versus 61.7 years). Nutritional status and stage were better in high dose group with a lower weight loss (5.1 versus 7.9%), a higher body mass index (25.7 versus 22.9), more N0 patients (60.2 versus 31.7%) and less stage III (27.7 versus 63.3%). Median follow up was 20.8 months (2.8-92.4 months), and 64.9 months (4.2-92.4 months) for the 33 surviving patients. No statistically significant difference was shown for local/locoregional control, disease-free survival. Overall survival at 2-, 3- and 5-year and median survival was respectively 44.7%, 36.8%, 19.1% and 21.2 months in high dose group and 50.8%, 31.6%, 20.7% and 24.6 months in standard dose group (P=0.9). CONCLUSION: No difference was found between the two groups in terms of local/distant control and overall survival. A prospective randomised study is needed.